DE3112055A1 - BISPIDINE DERIVATIVES, THEIR PRODUCTION AND THE MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Abstract

Bispidine derivatives of the formula I <IMAGE> I where R is hydrogen or amino, and their salts with physiologically tolerated acids. The compounds have antiarrhythmic properties.

Description

BASF Aktiengesellschaft 0.Z. 0050/035042

Bispidine derivatives, their preparation and containing them

drug

The invention relates to new bispidine derivatives, their production and pharmaceuticals that contain these new substances contain.

It is already known that a number of bispidine derivatives have antiarrhythmic properties (cf. K) DE-OS 24 28 792, DE-OS 27 26 571, J.Med.Chem. 20, 1668 (1977)).

Two new bispidine derivatives have now been found which outperform the known derivatives in their effectiveness. 15th

The invention relates to new bispidine derivatives Formula I.

where R is a hydrogen atom or an amino group, and their salts with physiologically acceptable acids.

Physiologically acceptable acids are s.B. in Question: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, Citric acid, tartaric acid, lactic acid and diamido

sulfonic acid.
30th

The invention also relates to a process for the preparation of the bispidine derivatives of the formula I and their Salts with physiologically acceptable acids, which consists in the fact that N-monobenzylbispidine with a

Compound of formula II

II »

wherein R is a halogen atom and

R em is a hydrogen atom or a nitro group

ρ
mean, and, if R represents a nitro group, this is reduced and the compounds thus obtained are optionally converted into their salts with physiologically acceptable acids.

The implementation of N-monobenzylbispidine with the compounds II can, for example, with sodium hydride in dimethylformamide; Sodium hydroxide in water or ethanol; Sodium carbonate in butanol or amyl alcohol; Potassium carbonate in water, methanol, ethanol, isopropanol, butanol, Amyl alcohol, acetone, acetonitrile, toluene, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran; Sodium methylate in methanol; Sodium isopropoxide in isopropanol; Potassium tert-butoxide in tert. Butanol, tetrahydrofuran or dimethyl sulfoxide; Sodium amide can be done in toluene or xylene. The reaction works best with sodium hydride in dimethylformamide. It is usually carried out at room temperature.

The reduction of any nitro group that may be present is best carried out catalytically with hydrogen. Platinum is particularly suitable as a catalyst.

Lower alcohols, in particular ethanol, can be used as solvents.

Finally, the invention relates to medicaments which contain the bispidine derivatives of the formula I or their salts

Contains physiologically compatible acids. 35

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"The new compounds can be administered orally or in the usual manner administered parenterally (intravenously, intramuscularly, intraperitoneally).

The dosage depends on the age, condition and weight of the patient and the type of application. Usually is the daily dose of active ingredient between about 0.5 and 10 mg / kg body weight for oral administration and between about 0.01 and 1.0 mg / kg body weight for parenteral administration. Normally, daily doses of 1 up to 5 mg / kg orally and 0.02 to 0.1 mg / kg parenterally achieved satisfactory results.

The new compounds can be used solid or liquid in the usual galenic administration forms e.g. as tablets, pilm tablets, capsules, powders, granulates, coated tablets, suppositories or solutions. These are produced in the usual way. The active ingredients can be combined with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, Plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents and / or Antioxidants are processed (see L.G. Goodman, A. Gilman: The Pharmacological Basis of Therapeutics). The active ingredients obtained in this way normally contain the active ingredient in an amount of 0.1 to 99 wt.

The new compounds and their salts have valuable pharmacological properties. They are highly antiarrhythmic effective and therefore particularly useful for pharmacotherapy suitable for cardiac arrhythmias.

The following examples illustrate the invention. 35

BASF Aktiengesellschaft —4— O.2.OO50 / O35O42

example 1

a) N- (4-nitrobenzoyl) -N'-benzylbispidine

18.8 g (0.43 mol) of a 55% sodium hydride suspension were added to a solution of 84.7 g (0.392 mol) of monobenzylbispidine in 8OO ml of dimethylformamide. After stirring for five hours at room temperature, a solution of 72.7 g (0.392 mol) of 4-nitrobenzoyl chloride in 200 ml of dimethylformamide was added dropwise and the mixture was stirred for a further three hours. The excess sodium hydride was decomposed with methanol. After the solvents had been distilled off in vacuo, the residue was taken up in water and extracted immediately with ether. After drying with sodium sulfate, the ether was evaporated. The residue 118.0 g (82.5%) of N- (4-obtained NitrobenzoylJ-N'-benzylbispidin. Pp. 125 to 127 ⁰ C.

b) N- (4-aminobenzoyl) -N ^t -benzylbispidine-1,5-fumarate

118.0 g of N- (4-nitrobenzoyl) -N'-benzylbispidine were dissolved in 1700 ml of ethanol and, after addition of 5 g of 5 % Pt / C, hydrogenated in a 2 l flask with stirring. When the hydrogen uptake had ended, the catalyst was filtered off and evaporated. The residue was dissolved in 1000 ml of hot isopropanol, and 56.2 g of fumaric acid were added. On cooling the solution, 124.0 g (81 %) of N- (4-aminobenzoyl) -N'-benzylbispidine-1,5-fumarate crystallized out. Pp. 151-153 ⁰ C

BASF Aktiengesellschaft - "$ - 'O.Z.0050 / 035042

Example 2

Analogously to example la), N-benzoyl-N'-benzylbispidine sulfate, melting point 18 ° C., is obtained in a yield of 76.2 %. 5

Example 3

Tablets of the following composition are pressed in the usual way on a tablet press: 10

50 mg of N- (4-aminobenzoyl) -N'-benzylbispidine 120 mg of corn starch
13.50 mg gelatin
45 n \ g milk sugar
22.5 mg talc

2.25 mg Aerosil® (chemically pure silica in submicroscopic finely divided) 6.75 mg potato starch (as 6 Jiiger paste)

Example 4

In the usual way, coated tablets are made with the following composition:

30 mg of N-benzoyl-N'-benzyl bispidine
6o mg core mass
d0 mg saccharification mass

The core mass consists of 9 parts of corn starch, 3 parts of lactose and 1 part of Luviskol® VA 64 (vinylpyrrolidone-vinyl acetate copolymer 60:40, cf. Pharm. Ind. 1962 , 5S6). The saccharification mass consists of 5 parts cane sugar, 2 parts corn starch, 2 parts calcium carbonate and 1 part talc. The coated tablets produced in this way are then provided with an enteric coating.

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BASF Aktiengesellschaft. . * _ 0.2. 0050/035042

example

10 g of N-C ^ -aminobenzoyD-N'-benzylbispidine are in 5000 ml of water with the addition of NaCl and an equimolar 5 ren amount of acetic acid dissolved, so that a blood isotonic Solution emerges. In each case 5 ml of the solution are filled into ampoules and sterilized.

Claims (7)

BASF Aktiengesellschaft 0. Z. 0050/035042 'Patent claims 1. Bispidine derivatives of the formula I.
R- <wVcoV \ VcH.-C ^ I, where R is a hydrogen atom or an amino group, as well as their salts with physiologically acceptable acids.
10 2. H- (4-aminobenzoyl) -N'-benzylbispidine 3. N-Benzoyl-N'-benzylbispidine 4. A process for the preparation of the bispidine derivatives of the formula I and their salts with physiologically acceptable acids, characterized in that N-monobenzyl bispidine with a compound of the formula II ι / - \ 'S II, wherein R is a halogen atom and
R is a hydrogen atom or a nitro group mean, and, if R represents a nitro group, this is reduced and the resulting Compounds optionally converted into their salts with physiologically acceptable acids. 30th 5. Medicaments containing a compound of the formula I according to claim 1. 101/81 WK / sk 03/25/81 BASF Aktiengesellschaft - 2 - 0.2.0050 / 035042 ^r 6. Use of a compound of the formula I according to claim 1 in the fight against heart disease. 7. Compound of formula I according to claim 1 for Ver-5 application in the healing of heart disease.